The biochemistry The biochemistry of of

cell injury and cell cell injury and cell deathdeathDr Stephany VeugerDr Stephany Veuger

OverviewOverviewPart APart A Review causes of cellular damageReview causes of cellular damage Types of cellular damageTypes of cellular damage Mechanisms of cell deathMechanisms of cell death Biochemical events that lead to cell Biochemical events that lead to cell

deathdeathPart BPart B Free radicalsFree radicals Diseases associated with free radical Diseases associated with free radical

damagedamage

Learning OutcomesLearning Outcomes

Understand how the basic functions Understand how the basic functions of the cell are affected by injuryof the cell are affected by injury

Discuss morphological and Discuss morphological and biochemical changes in response to biochemical changes in response to injuryinjury

Be able to explain the types of cell Be able to explain the types of cell deathdeath

Describe the biochemical changes in Describe the biochemical changes in response to ischaemiaresponse to ischaemia

Causes of cell injuryCauses of cell injury

PhysicalPhysical Chemical Chemical InfectiousInfectious ImmunologicImmunologic Genetic derangementGenetic derangement Nutritional and Oxygen ImbalancesNutritional and Oxygen Imbalances Metabolic changes Metabolic changes

Cellular damageCellular damage

SUBLETHALSUBLETHAL Damage is minimalDamage is minimal Recovery Recovery

LETHALLETHAL Continued damage Continued damage Damage is massive Damage is massive

Mechanisms of cell Mechanisms of cell injuryinjury

Injurious agents can affect the cell at Injurious agents can affect the cell at a number of levels by damaging :a number of levels by damaging :

Plasma membranePlasma membrane Aerobic respiration and ATP Aerobic respiration and ATP

productionproduction Protein synthesisProtein synthesis Genetic machineryGenetic machinery

Morphological indicators of Morphological indicators of

cell injurycell injury Alterations to plasma membrane Alterations to plasma membrane Cytoskeleton damageCytoskeleton damage Mitochondrial condensationMitochondrial condensation Mitochondrial swellingMitochondrial swelling Dilatation of ERDilatation of ER Ribosome detachmentRibosome detachment Alterations to lysosomesAlterations to lysosomes

Morphological changes Morphological changes following sub-lethal injuryfollowing sub-lethal injury

Mitochondrial swelling (low amplitude Mitochondrial swelling (low amplitude swelling) swelling)

-vacuoles distort cristae-vacuoles distort cristae

-reversible-reversible ER swellingER swelling

-loss of ribosomes-loss of ribosomes High amplitude swellingHigh amplitude swelling

-cristae destroyed-cristae destroyed

--irreversibleirreversible

ATP-dependent ATP-dependent processes affectedprocesses affected

Morphological changes Morphological changes following sub-lethal injuryfollowing sub-lethal injury

Under the microscope, these changes are seen Under the microscope, these changes are seen as;as;

Cellular swellingCellular swelling Pale cytoplasmPale cytoplasm Small intracellular vacuolesSmall intracellular vacuolesCLOUDY SWELLING or HYDROPIC CLOUDY SWELLING or HYDROPIC

DEGENERATIONDEGENERATION

Accumulation of lipidAccumulation of lipidFATTY CHANGEFATTY CHANGE

Fatty ChangeFatty Change

Deficiency in lipid acceptor proteins, Deficiency in lipid acceptor proteins, preventing export of formed triglyceridespreventing export of formed triglycerides-carbon tetrachloride, malnutrition, hypoxis-carbon tetrachloride, malnutrition, hypoxis

Increased mobilisation of free FA into cells Increased mobilisation of free FA into cells - diabetes mellitus and nutritional deprivation- diabetes mellitus and nutritional deprivation

Increased conversion of fatty acids to Increased conversion of fatty acids to triglyceridestriglycerides-alcohol abuse-alcohol abuse

Reduced oxidation of triglycerides to acetyl-Reduced oxidation of triglycerides to acetyl-coAcoA-hypoxia, toxins-hypoxia, toxins

Cell survivalCell survival- Following injury, major cellular Following injury, major cellular

components need to be maintained to components need to be maintained to promote survival ;promote survival ;

Cell membranesCell membranes MitochondriaMitochondria CytoskeletonCytoskeleton Cellular DNACellular DNA

- These systems are not interdependent - These systems are not interdependent - Threshold – death - Threshold – death

Plasma membranePlasma membrane

Integrity following injury is Integrity following injury is ESSENTIALESSENTIAL

Direct Direct Failure of phospholipid biosynthesisFailure of phospholipid biosynthesis Particularly vulnerable to free Particularly vulnerable to free

radical attackradical attack Degradation of phospholipids by Degradation of phospholipids by

Ca2+ dependent phospholipasesCa2+ dependent phospholipases

Morphological changes Morphological changes following lethal injury following lethal injury

High amplitude swellingHigh amplitude swelling

Morphological changes to the nucleusMorphological changes to the nucleus

Appearance of membrane blebs and holesAppearance of membrane blebs and holes

Dissolution of the nucleusDissolution of the nucleus

Distinct structural changes to cell leading to Distinct structural changes to cell leading to dissolution of cell via release of lysosomal enzymesdissolution of cell via release of lysosomal enzymes

AUTOLYSISAUTOLYSIS

Morphological changes Morphological changes following lethal injury following lethal injury

(nucleus)(nucleus) PYKNOSISPYKNOSIS

-condensation of nuclear chromatin-condensation of nuclear chromatin Loss of nucleolusLoss of nucleolus KARRYORRHEXISKARRYORRHEXIS

-fragmentation of the nucleus-fragmentation of the nucleus KARYOLYSISKARYOLYSIS

-complete dissolution of nuclear -complete dissolution of nuclear materialmaterial

Summary ISummary I Cell have limited capacity to adapt to change Cell have limited capacity to adapt to change

Mild injury can be accommodated by cells but Mild injury can be accommodated by cells but is evident by biochemical and morphological is evident by biochemical and morphological changeschanges

Sub-lethal –reversible Sub-lethal –reversible Injury that is sufficient to cause morpholgical Injury that is sufficient to cause morpholgical

changes to the nucleus is usually lethalchanges to the nucleus is usually lethal Dissolution of nuclear and cytoplasmic contents Dissolution of nuclear and cytoplasmic contents

is caused by the release of lysosomal enzymesis caused by the release of lysosomal enzymes

Cell deathCell death

-Follows irreversible cell damage-Follows irreversible cell damage

-Can be by accident or design-Can be by accident or design

ApoptosisApoptosis NecrosisNecrosis

Different morphological changes Different morphological changes

ApoptosisApoptosis

Routine – repair and cell cycle (p53)Routine – repair and cell cycle (p53)

Programmed – co-ordinated- Programmed – co-ordinated- “shrinkage”“shrinkage”

Stimuli mediated by immune system ; Stimuli mediated by immune system ; cytokinescytokines

Autophagy (self digestion)Autophagy (self digestion)

NecrosisNecrosis

Massive damage to cellular systems Massive damage to cellular systems

Uncontrolled loss of large numbers of Uncontrolled loss of large numbers of cellscells

Extensive organelle and cell “swelling”Extensive organelle and cell “swelling”

Rupture of plasma membrane and Rupture of plasma membrane and dissolution of the celldissolution of the cell

Biochemical determinants Biochemical determinants of necrotic changeof necrotic change

ATP ATP Calcium homeostasisCalcium homeostasis pHpH Reactive Oxygen Species (ROS)Reactive Oxygen Species (ROS) Intracellular antioxidant levelsIntracellular antioxidant levels

ATPATP

Produced by cellular respirationProduced by cellular respiration biosynthesisbiosynthesis Critical for function of many Critical for function of many

transport pumpstransport pumps Critical for cell signalling processesCritical for cell signalling processes Cloudy swelling and fatty change Cloudy swelling and fatty change

CalciumCalcium Normal concentration in cytosol very lowNormal concentration in cytosol very low

-rapidly removed by ATP-dependent pumps-rapidly removed by ATP-dependent pumps

-bound to buffering proteins (calbindin, -bound to buffering proteins (calbindin, parvalbumin)parvalbumin)

Increased intracellular calcium brought about Increased intracellular calcium brought about by;by;

-↑permeability of Ca2+ channel-↑permeability of Ca2+ channel

-direct membrane damage-direct membrane damage

-ATP depletion-ATP depletion

-mitochondrial damage-mitochondrial damage

Cytosolic free calcium is a Cytosolic free calcium is a potent destructive agentpotent destructive agent

CALCIUM STORESMitochondria

ER lumenPumped to extracellular

spaceBound to binding proteins

Released following cell injury

FREE Ca 2+

Activation of ATPases

Activation ofphospholipases

Activation ofproteases

Membranedamage

Destabilising of cytoskeleton

Reduced ATP

Reative Oxygen species Reative Oxygen species (ROS)(ROS)

Most important free radicals in the Most important free radicals in the body are the oxygen-derived free body are the oxygen-derived free radicalsradicals

Attack bio-moleculesAttack bio-molecules

Lipid peroxidation - decreases Lipid peroxidation - decreases membrane fluidity and destabilises membrane fluidity and destabilises membrane receptors.membrane receptors.

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Effect of ROS on biomolecules

Changes in metabolismChanges in metabolism

Accumulation of materials as a Accumulation of materials as a result of changes in metabolism may result of changes in metabolism may compromise normal function of cellcompromise normal function of cell

Lipid (fatty change already covered)Lipid (fatty change already covered) Protein –kidneys, reversibleProtein –kidneys, reversible Carbohydrate-diabetes, glycogen Carbohydrate-diabetes, glycogen

storage disordersstorage disorders pigmentspigments

ISCHAEMIAISCHAEMIA

Excellent example of the cellular Excellent example of the cellular response to a damaging stimulusresponse to a damaging stimulus

ISCHAEMIA = LACK OF OXYGEN ISCHAEMIA = LACK OF OXYGEN SUPPLYSUPPLY

HYPOXIA =LACK OF OXYGENHYPOXIA =LACK OF OXYGEN

DefinitionsDefinitions

HYPOXIAHYPOXIA

-decrease in oxygen in arterial blood or -decrease in oxygen in arterial blood or tissuestissues

ISCHAEMIAISCHAEMIA

-local anaemia, leading to hypoxia eg. -local anaemia, leading to hypoxia eg. Obstruction to blood flow to organ/tissueObstruction to blood flow to organ/tissue

INFARCTIONINFARCTION

-sudden insufficiency of blood supply -sudden insufficiency of blood supply producing macroscopic areas of necrosis producing macroscopic areas of necrosis (eg. MI)(eg. MI)

Biochemical and Biochemical and morphological changes due morphological changes due

to Ischaemia (I)to Ischaemia (I) Shift from aerobic to anaerobic respirationShift from aerobic to anaerobic respiration Reduction in ATPReduction in ATP Failure of ATP-dependent pumps (Na+/K+, Failure of ATP-dependent pumps (Na+/K+,

ATPase and Ca2+)ATPase and Ca2+) Failure to maintain intracellular ionic Failure to maintain intracellular ionic

balancebalance Accumulation of Na+ in cytoplasmAccumulation of Na+ in cytoplasm Ingress of calcium and water and outflow Ingress of calcium and water and outflow

of potassium ionsof potassium ions

Cloudy Swelling and disruption of Cloudy Swelling and disruption of internal membrane systemsinternal membrane systems

Biochemical and Biochemical and morphological changes due morphological changes due

to Ischaemia (II)to Ischaemia (II)Integrity of RER relies on Na+ pumpIntegrity of RER relies on Na+ pump

ribosomes detachribosomes detach Protein synthesis ceasesProtein synthesis ceases Calcium – activation of several Calcium – activation of several

destructive enzyme systems destructive enzyme systems Phospholipid synthesis ceasesPhospholipid synthesis ceases

Further disruption of membranesFurther disruption of membranes

Biochemical and Biochemical and morphological changes due morphological changes due

to Ischaemia; pH (III)to Ischaemia; pH (III) Anaerobic respiration results in Anaerobic respiration results in

lactic acid productionlactic acid production Intracellular pH decreasesIntracellular pH decreases Membranes under acid attackMembranes under acid attack pH further augmented via phosphate pH further augmented via phosphate

ions produced by Ca2+ activated ions produced by Ca2+ activated phosphatasesphosphatases

Fall in pH stimulates pyknosisFall in pH stimulates pyknosis

Biochemical and Biochemical and morphological changes due morphological changes due

to Ischaemia; pH (IV)to Ischaemia; pH (IV) LysosomesLysosomes Release of destructive enzymes leads to Release of destructive enzymes leads to

karryhrrexis and karyolyisskarryhrrexis and karyolyiss Cell deathCell death Neighbouring cells injuredNeighbouring cells injured

Initial changes in ischaemia reversible Initial changes in ischaemia reversible but nuclear changes catastrophic for but nuclear changes catastrophic for cellcell

ISCHAEMIAISCHAEMIA

Reduced oxidative phosphorylation

Anaerobic respiration

Potassium

Water

Calcium

?ATPDecrease in sodium pump

Lactic acid

?lysosomes

Cell death

? pHribosomes detach

? Protein synthesis

??

?

ISCHAEMIAISCHAEMIA

Reduced oxidative phosphorylation

Anaerobic respiration

Potassium

Water

Calcium

?ATPDecrease in sodium pump

Lactic acid

?lysosomes

Cell death

? pHribosomes detach

? Protein synthesis

??

?

ISCHAEMIAISCHAEMIA

Reduced oxidative phosphorylation

Anaerobic respiration

Potassium

Water

Calcium

ATPDecrease in sodium pump

Lactic acid

lysosomes

Cell death

pHribosomes detach

Protein synthesis

pyknosis

karyorrhexis

karyolysis

Summary IISummary II

Cells die by two main pathwaysCells die by two main pathways

Biochemical determinants of injury Biochemical determinants of injury and death ATP, Ca2+, pH, ROS and death ATP, Ca2+, pH, ROS

Ischaemia most common injury in Ischaemia most common injury in clinical medicineclinical medicine

The role of free radicals and anti-oxidant mechanisms

in health and disease

OverviewOverview

What are free radicals?What are free radicals? Sources of free radicalsSources of free radicals Types of free radicals (ROS)Types of free radicals (ROS) Types of free radical damageTypes of free radical damage Diseases associated with free Diseases associated with free

radicalsradicals Anti-oxidant mechanismsAnti-oxidant mechanisms

Learning OutcomesLearning Outcomes

Define the terms free radical and reactive Define the terms free radical and reactive oxygen speciesoxygen species

Characterise the major reactive oxygen Characterise the major reactive oxygen species and their sourcesspecies and their sources

Discuss the negative effects of ROS on bio-Discuss the negative effects of ROS on bio-molecules molecules

Describe the cellular defence mechanisms Describe the cellular defence mechanisms against free radicalsagainst free radicals

What is a free radical?What is a free radical?

A radical is an atom or molecule A radical is an atom or molecule with one or more unpaired electronswith one or more unpaired electrons

A radical that can move freely within A radical that can move freely within cell and across membranes is a free cell and across membranes is a free radicalradical

Highly unstable and extremely Highly unstable and extremely reactivereactive

Free radicalsFree radicals

Most molecules found in the body Most molecules found in the body are not radicals. are not radicals.

Any reactive FR generated will often Any reactive FR generated will often react with such non-radicals i.e. react with such non-radicals i.e. sugars, amino acids, phospholipids, sugars, amino acids, phospholipids, nucleotides, polysaccharides, nucleotides, polysaccharides, proteins, nucleic acids etc.proteins, nucleic acids etc.

When this happens, a When this happens, a free radical free radical chain reactionchain reaction resultsresults

Sources of free radicalsSources of free radicals

Ionising radiationIonising radiation Chemicals Chemicals Exposure to excess oxygenExposure to excess oxygen

Cell respirationCell respiration InflammationInflammation

Ionising radiation Ionising radiation

H2O

Ionising radiationenergy (hV)

OH + H. .

Hydroxyl radical

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Reactive oxygen species (ROS)

OO22-•-•

HH22OO22

OHOH••

RORO••

RCOORCOO••

HOClHOCl

SuperoxideSuperoxide leakage from the electron transport leakage from the electron transport chain is the main sourcechain is the main source

Hydrogen Hydrogen peroxideperoxide

Not a free radical itself, but is Not a free radical itself, but is dangerous because in the presence of dangerous because in the presence of a transition metal it quickly produces a transition metal it quickly produces OHOH••

Hydroxyl Hydroxyl radicalradical

Generated from HGenerated from H22OO2 2 by Fenton by Fenton reactionreaction

Organic radicalOrganic radical Usually produced from C=C bondsUsually produced from C=C bonds

Peroxyl radicalPeroxyl radical Generated when radicals attack lipidsGenerated when radicals attack lipids

Hypochlorous Hypochlorous acidacid

Generated on purpose as part of Generated on purpose as part of immune “respiratory burst”immune “respiratory burst”

AbstractionAbstraction

Stripping of electrons from other atoms Stripping of electrons from other atoms or moleculesor molecules

R• + HB RH + B•

Propogation

H abstraction on sugars such as deoxyribose yields many products, some of which are mutagenic.

H abstraction on unsaturated membrane lipids is one of the most important aspects of damage to cells by FRs.

AdditionAddition

Attack of hydroxyl radical on DNA Attack of hydroxyl radical on DNA bases bases

Thymine + OH● Thymine + OH● Thymine-OH●Hydroxythymine radical

Thymine-OH● + OH● Thymine glycol

Effect of ROS on biomolecules

Effect on lipidEffect on lipid Peroxidation of membrane lipids is the Peroxidation of membrane lipids is the

most important cause of serious acute most important cause of serious acute damage to cells damage to cells Malondialdehyde = marker for oxidative Malondialdehyde = marker for oxidative

stressstress

chain reaction of lipid peroxidationchain reaction of lipid peroxidation- H abstraction from a polyunsaturated H abstraction from a polyunsaturated

fatty acid in a membrane or lipoproteinfatty acid in a membrane or lipoprotein- Introduction of a polar group –OOH Introduction of a polar group –OOH

into hydrophobic regioninto hydrophobic region- Attack of one reactive FR can oxidise Attack of one reactive FR can oxidise

multiple fatty acid side chains to multiple fatty acid side chains to lipid lipid peroxidesperoxides

Effect on DNAEffect on DNA

Reactive FRs such as the hydroxyl radical Reactive FRs such as the hydroxyl radical can react with both the deoxyribose and can react with both the deoxyribose and the bases of DNAthe bases of DNA

TheThe sugar component will be affected by sugar component will be affected by H abstractionH abstraction, resulting in many , resulting in many products, many of which are products, many of which are mutagenicmutagenic..

Bases can be affected by Bases can be affected by additionaddition reactions, ultimately leading to reactions, ultimately leading to mutationmutation and and cellularcellular derangementderangement

Depletion of NADH poolsDepletion of NADH pools

Effect on proteinsEffect on proteins

Formation of disulphide bridges by Formation of disulphide bridges by oxidation of the thiol groups (-SH) of oxidation of the thiol groups (-SH) of cysteine residuescysteine residues

Attack metal binding sites leading to Attack metal binding sites leading to degradation by proteasesdegradation by proteases

Loss of biological activity eg enzymesLoss of biological activity eg enzymes Malondialdehyde - protein adducts or Malondialdehyde - protein adducts or

advanced lipoxidation end products advanced lipoxidation end products (APE)(APE)

Effect on carbohydratesEffect on carbohydrates

Hydroxyl radical - H abstractionHydroxyl radical - H abstraction

Depolymerisation of hyaluronic acid Depolymerisation of hyaluronic acid -Synovial fluid viscosity-Synovial fluid viscosity

ROS as a protective ROS as a protective mechanismmechanism

Peroxisome has highest concentration of Peroxisome has highest concentration of FRsFRs

Phagocytes use the generation of FRs in Phagocytes use the generation of FRs in phagosome to attack and destroy bacteriaphagosome to attack and destroy bacteria

RESPIRATORY BURST –rapid use of RESPIRATORY BURST –rapid use of oxygen to generate FRsoxygen to generate FRs

Problem during e.g. MI. Designed to Problem during e.g. MI. Designed to remove dead cells but causes local remove dead cells but causes local inflammationinflammation

The superoxide radicalThe superoxide radicalO2●-O2●-

Generated during electron transport Generated during electron transport chain chain

Oxidase enzymesOxidase enzymes

O2 O2●-O2 O2●-oxidase

The hydroxyl radicalThe hydroxyl radical OH● OH●

An extremely reactive species An extremely reactive species Reacts with great speed with Reacts with great speed with

whatever molecules are in its whatever molecules are in its vicinityvicinity

Responsible for many of the effects Responsible for many of the effects of high level radiation in the human of high level radiation in the human bodybody

Can be formed by fenton reaction Can be formed by fenton reaction

Promoters of free radical Promoters of free radical damage : Metal ionsdamage : Metal ions

Iron and copper Iron and copper Encourage formation of hydroxyl radicalEncourage formation of hydroxyl radical

FeFe2+2+ + H + H22O O

Iron conjugated to protein and stored as Iron conjugated to protein and stored as ferritin/ transported as transferrinferritin/ transported as transferrin

Copper is transported as caeruloplasminCopper is transported as caeruloplasmin

Free ions = Free ions = pro-oxidantspro-oxidants

Fe3+ + OH● + OH

Free Radicals and Free Radicals and diseasedisease

Accumulation of damaged proteins, Accumulation of damaged proteins, carbohydrates, lipids andcarbohydrates, lipids and

nucleic acids contributes to a wide range of nucleic acids contributes to a wide range of human diseaseshuman diseases

FR damage Cell injury

Apoptosis Necrosis Ageing CancersAthero-sclerosis

Degenerativediseases

Cell death

FRs and cardiovascular FRs and cardiovascular diseasedisease

There is growing evidence that lipid There is growing evidence that lipid peroxidation occurs in blood vessel peroxidation occurs in blood vessel wallswalls

Contributes to the development of Contributes to the development of atherosclerosisatherosclerosis raising the risk of raising the risk of stroke and myocardial infarction.stroke and myocardial infarction.

LipofushinLipofushin

Free radicals in cancerFree radicals in cancer

FRs can severely damage DNA of FRs can severely damage DNA of cells which can lead to abnormal cells which can lead to abnormal cells & cancer growth cells & cancer growth

FRs can convert certain chemicals FRs can convert certain chemicals into carcinogensinto carcinogens

DNA repair / apoptois DNA repair / apoptois

-Hydroxyguanine -Hydroxyguanine

Summary ISummary IFree radicalsFree radicals

Extremely reactive chemical species with an unpaired electronExtremely reactive chemical species with an unpaired electron

Produced in cells as metabolic by-productsProduced in cells as metabolic by-products

Produced by phagocytic cells as part of inflammatory defencesProduced by phagocytic cells as part of inflammatory defences

Produced by the action of toxic compoundsProduced by the action of toxic compounds

Cause cell injuryCause cell injury

Caused by cell injuryCaused by cell injury

Summary IISummary IIFree radicalsFree radicals

Free radicals can cause oxidative damage Free radicals can cause oxidative damage to cells componentsto cells components

The most dangerous free radical is the The most dangerous free radical is the hydroxyl ionhydroxyl ion

Damage by free radicals is believed to Damage by free radicals is believed to contribute to the pathogenesis of many contribute to the pathogenesis of many chronic diseaseschronic diseases

AntioxidantsAntioxidants

Defence systems Defence systems

1) Directly – blocking formation or 1) Directly – blocking formation or scavengingscavenging

2) Binding metals that catalyse ROS 2) Binding metals that catalyse ROS formationformation

3) Enzyme activity 3) Enzyme activity

Intracellular Intracellular antioxidantsantioxidants

Glutathione Glutathione peroxidaseperoxidase

Removes hydrogen Removes hydrogen peroxideperoxide

Selenium dependentSelenium dependent

Cytosol and Cytosol and mitochondriamitochondria

GlutathioneGlutathione Scavenger of hydroxyl Scavenger of hydroxyl radicalradical

Superoxide Superoxide dismutasedismutase

Catalyses conversion of Catalyses conversion of superoxide to hydrogen superoxide to hydrogen peroxideperoxide

CatalaseCatalase Removes hydrogen Removes hydrogen peroxideperoxide

Dietary antioxidantsDietary antioxidants

Vitamin E (Vitamin E (αα--tocopherol)tocopherol)

Inhibits lipid Inhibits lipid peroxidationperoxidation

Vitamin C (ascorbic Vitamin C (ascorbic acid)acid)

Inhibits pro-oxidantsInhibits pro-oxidants

Vitamin A (Vitamin A (ββ--carotene)carotene)

Lipid soluble radical Lipid soluble radical scavengerscavenger

ZincZinc Component of Component of superoxide dismutasesuperoxide dismutase

ManganeseManganese Component of Component of superoxide dismutasesuperoxide dismutase

Copper Copper Component of Component of superoxide dismutasesuperoxide dismutase

SeleniumSelenium Component of Component of glutathione peroxidaseglutathione peroxidase

Antioxidant enzymesAntioxidant enzymes

Superoxide dismutase converts superoxide Superoxide dismutase converts superoxide to hydrogen peroxide and oxygento hydrogen peroxide and oxygen

OO22●- + O●- + O22●- + 2H ●- + 2H

catalase and glutathione peroxidase convert catalase and glutathione peroxidase convert hydrogen peroxide to water and oxygen hydrogen peroxide to water and oxygen

2H2H22OO22

H2O2 + O2

O2 + H2O

Free radical theory of Free radical theory of ageingageing

Summary IIISummary IIIAntioxidantsAntioxidants

Maintenance of cell integrity Maintenance of cell integrity depends on a balance between FR depends on a balance between FR activity and antioxidant statusactivity and antioxidant status

Fat-soluble antioxidant vitamins are Fat-soluble antioxidant vitamins are essential for controlling lipid essential for controlling lipid peroxidationperoxidation

Diet rich in fruit and vege may Diet rich in fruit and vege may prevent diseaseprevent disease